The virulence of influenza virus strains has been linked to their ability to disengage cellular innate antiviral responses. One current antiviral therapeutic strategy for emerging influenza strains involves the use of RNA silencing techniques, and this approach has already shown great promise in the treatment of influenza virus infections. This proposal is designed to use influenza virus infections as a means to explore the interaction and crosstalk between two innate antiviral systems triggered by intracellular double stranded RNA (dsRNA). RNA interference (RNAi) is an intrinsic dsRNA-mediated gene silencing system that is central to cellular gene regulation in the plant and animal kingdoms. RNAi is a potent innate antiviral system central to pathogen defenses in plants and lower animals, and has been harnessed as a therapeutic strategy for human diseases. In vertebrates, the type I interferons induce a potent cellular antiviral response. The IFN genes originated by duplication of a progenitor after the divergence of birds approximately 250 million years ago. The antiviral contributions of RNA silencing are less pronounced in vertebrates, and dsRNA based innate immune response genes may have arisen from components of the RNA silencing system. It is the central hypothesis underlying this proposal is that these two ancient dsRNA processing systems are functionally integrated in the regulation of cellular innate antiviral immune responses in human cells. The interdependence and cross-regulation between these two RNA processing systems is the focus of this exploratory application. Two complementary specific aims are proposed to test the link between IFN antiviral signaling and RNA silencing in the context of influenza virus infections. [unreadable] [unreadable] [unreadable] [unreadable]